A striking feature of human viral infections is the heterogeneity of host response to exposure, infection, and disease outcome. The objective of this project is to discover and characterize human genetic loci operative in differential host response to two pathological viruses, HIV and hepatitis B virus, using the combined methods of human molecular genetics, population genetic theory, and epidemiology. Distortions of population genetic equilibrium in DNA samples from epidemiological cohorts will be used to identify loci that influence the outcome of HIV exposure. A panel of 320 polymorphic loci (200 restriction fragment length polymorphisms and 120 candidate genes) spaced at approximately 10-centiMorgan intervals across all chromosomes are being typed on patients classified into dichotomous risk categories. Collaborations have been formalized with eight multicenter epidemiologic cohorts of HIV-exposed participants and two hepatitis cohorts in Taiwan and People's Republic of China. More recent cohorts have a high frequency of mixed human racial grouping, particularly useful for Polymorphism Admixture Typing (PAT) to enhance associated linkage disequilibrium. An HLA epistatic interaction between Class II and TAP genes with AIDS progression has been described. Several non-HLA distortions have been associated with resistance to disease progression to AIDS. These distortions are significant associations that represent the first signal in defining non-HLA restriction genes.